Glandular extractive product.



UNITED STATE JOKICHI TAKA'MINE,

OF NEWV YORK, N. Y.,@

i GLANDULAR EXTRACTIVE PRODUCT.

SPECIFICATION forming part of Letters Patent No. 730,176, dated June 2,1903.

Original application filed November 5,1900, Serial No. 35,546. Dividedand this application filed January 14, 1903. Serial.

No. 138,969. (No specimens.)

To a, whom it may concern:

Be it known that I, J OKICHI TAKAMINE, a subject of the Emperor ofJapan, residing in the city of New York, county and State of New York,have invented and prodnced a -new and useful Glandular Extractive Product, of which the following is a specification.

My invention relates to a new and useful product which possesses in astable, permanent, and concentrated form the hemostaticblood-pressure-raising astringent and other physiological reactions andcharacteristics of the suprarenal capsules or glands, particularly thosewhich affect the muscular system and muscular walls of theblood-Vessels, said product being practically free from inert, de-

teriorating, or deleterious matter.

It has been known heretofore that the suprarenal glands possesshemostatio, bloodpressure-raising, and astringent properties,

and various attempts have been made to utilize them. For instance, theglands have been desiccated and powdered and employed The dried andpowdered in this condition. glands, as well as the glands in freshcondition, have been extracted with water and the aqueous extractutilized. Also attempts have been made to obtain the efficientconstituents of the glands above mentioned in a more or less segregatedcondition. All these attempts to utilize the above-described prop-'erties of the glands have failed to produce a stable, efficient, pure,concentrated, and reliable product, uniform and permanent in its actionand free from injurious and decomposing ingredients. For these reasonsand in View of the danger of introducing impurities and injurioussubstances into the human system it has hitherto been impracticable' toemploy the valuable properties of the glands, and the medical andsurgical arts have been deprived of an efficient and valutem.

The present application is a division of a former application, SerialNo. 35,546, filed November 5, 1900, in which is described a process forobtaining the herein-described product. v Other applicationsviz.,'Serial Nos. 37,729 and 37,730, filed November 26,

1900, and Serial No. 156,746, filed May 12,

1903-disclose other processes for obtaining theproduct forming thesubject of the present invention.

According to my application Serial N0. 35,546,0f November 5, 1900, theproduct is obtained as follows: The clean suprarenal glands orcapsulesof animalssuoh as cattle, sheep, '&c. are disintegrated by anysuitable means and a fluid extract is made therefrom by treatment of thedisintegrated glands with about an equal weight of water and steeping ata temperature of about to centigrade for a period of about five to tenhours in a suitable vessel, preferably avoiding contact with atmosphericair, which can be. to

a great extent accomplished by a film of fat floating on top of theliquid or may be done by passing a slow current of hydrogen or carbondioxid into the top part of the vesse'l. The film of fat referred to maybe the g fat associated with the glands in their natural condition. Theobject'of this protective film or atmosphere is to prevent the oxidationof the extract. I At the latter part of the steeping the temperature ofthe mixture may be raised from to centigrade. The mass, is now strained,and the residue is pressed to squeeze outas much liquid as possible. Theresidue thus pressed out is steeped again with the least amount of waterto cover the mass for several hours at the same temperature as above.The'two 'extracts thus obtained are mixed and the mixture is cooledrapidly and the solidified fat removed. The liquid is now evaporated ata low temperature, preferably in a vacuumpan, admitting,.if necessary, asmall quantity of hydrogen or carbon dioxid to replace air and toprevent oxidation. The liquidis evaporated until it becomes one-fifth tooneseventh of the original volume. To this concentrated solution two tothree times its own volume of alcoholis added, so that the mixr co tnrewill contain about sixty per cent. of alcohol, by volume. This additionof'alcohol will precipitate non-active bodies, such as albuminoids,phosphates, and other mineral salts. It is then filtered and thefiltrate distilled under vacuum to separate the alcohol, which iscondensed and recovered in a suitable manner. The liquid is thusconcentrated to such a degree that itsspecific gravity becomes 1.05 to1.15, and caustic-soda or caustic-potash solution of about thirty percent. strength is gradually and carefully added, taking due precautionnot to overheat the liquid until the mixture showsa strongalkalinereaction. At this stage an amount of ammonium chlorid corresponding toone-half of the molecular weight of the caustic soda used is added andmade to dissolve in the liquid. The solution is now allowed to remain ina cool place from twelve to fourteen hours, when the formation of acrystalline substance will be observed in this liquid, and its formationwill be completed during that space of time. This crystalline substancewill be found to consist of conglomerations of miorocrystals. Thequantity of caustic alkali to be added is regulated so that the alkaliadded will dissolve or redissolve the product formed, the quantity ofalkali used beingr about 0.3 to 0.4E per cent., in weight, of theoriginal gland used, and the amount of ammonium chlorid to be added isregulated in such a way that it will nullify the excess of the causticalkali used, it being understood that the solvent action is due to fixedcausticalkali and is not exerted by ammonia. The caustic alkali used maybe any of the substances generally recognized as of a causticalkalinenature, as the hydrates of sodium, potassium, calcium, barium, and thelike.

Instead of adding ammonium chlorid after the addition of the causticalkali carbon dioxid may be passed into the solution. Then the formationof white silky miorocrystals will be observed. The carbon dioxid ispassed until no more precipitate is formed. This substance is filteredout and washed with water and alcohol and dried. This constitutes theproduct of my invention.

In order to further purify the substance, the following methods may beused, namely: The crude mass is dissolved in the least amount possibleof weak acid, such as acetic or bydrochloric acid. The solution is thenfiltered, preferably after the addition of strong alcohol to precipitatemineral matters and other impurities and inert substances, ifneccessary, and caustic ammonia or alkaline carbonates are added, so asto make the solution strongly alkaline. The substance will then separateout in much purer form than before, being practically free frominorganic matter. This process of purification may be repeated until thesubstance becomes quite pure, or the crude substance may be dissolved inthe least possible amount of weak caustic alkali, filtered, ifnecessary, and carbon dioxid then passed into the solution. Thesubstance will precipitate out-,in a white crystalline condition. Thepurification may be repeated as often as necessary.

The substance or product is difficultlysoluble in water, dissolving morereadily in hot water than in cold, and this property can be utilized forits recrystallization. For this purpose the substance is heated withwater slowly to the boiling-point in presence of an excess of thesubstance. The liquid is filtered while hot, and the filtrate on coolingwill deposit the substance in fine crystalline form. It will crystallizeoutin tabular form or in triangular prism or fine needle form. Thesubstance is readily soluble in weak alkalies or in weak acids, organicas well as inorganic. With acids the substance forms saltscorresponding. to the acids. The salts are with difficulty crystallized,for the reason that they are hygroscopic. Salts of the substance possessthe same physiological properties as the substanceitself and constitutenew substances not claimed herein, but claimed in another application,Serial No. 156,747, filed May 12, 1903.

My new product is perfectly stable when pure and dry and can thereforebe kept for years without deterioration, thus affordinga permanent andreliable form embodying the Valuable properties of the suprarenal glandsin a highly-concentrated and powerful condition. The substance may bekept in the solid condition or in the form of a solution. To illustrateits properties, the following instances are cited: A drop of a solutionof my product of a strength of from one one-thousandth to one ten-thousandth will blaneh normal conjunctiva within a minute. An aqueoussolution of one one-thousandth water shows an approximately equalstrength with a fresh aqueous extract of fresh glands in the proportionof eight parts of the glands to ten of water. An intravenous injectionof the substance int-o an animal system produces a powerful action uponthe muscular system in general, more especially upon the muscular wallsof the blood-vessels, causing an enormous rise of blood-pressure.

The substance in its crystalline condition assumes a variety of forms,which is one of its characteristics. Among the forms which it assumesare polygonal prisms, fine needles, rhombic plates, boat or leafshaped,conglomerations of needles, and dumb-bell shaped. In color the substanceis whitish and has a melting-point of about 207 centigrade. Among itschemical characteristics may be enumerated the following: Toward theusual acid and alkaline test reageants its aqueous solution exhibits analkaline reaction. This is in distinction to the condition in which thesubstance exists in the glands, where it is either neutral or of an acidreaction. With ferric salts the substance gives a characterphomolybdicacid, phosphotungstic acid, mer-' green color. If when the greencoloration exists the solution be rendered alkaline, a beautiful rose orcarmine-red color is produced. Withiodin-water a red coloration isgiven. While the formula of the substance is not yet fixed positively,present determinations show it to be approximately O H NO The substanceis not precipitated by the usual alkaloid reagents, such-as mercurypotassium iodid, picric acid, tannic acid, phoscuric chlorid, leadacetate, potassium bichromate, platinum chlorid, potassium cadmiumiodid, potassium bismuth iodid, &c.

The substance possesses powerful reducing properties, reducing gold andsilver salts with great energy, particularly the former, the reactionupon the new product being to give it a beautiful rose-red color.

' The substance may be kept in solid form or in solution, and where inthe claims I have used the term substance I desire it to be understoodas referring to either the solid or solution form of the substance,except when such signification would be plainly inconsistout with theterms of a particular claim.

While other characteristics and properties of the substance might begiven, those mentioned above are sufficient to fully identify thesubstance.

Although the substance may be produced by the process herein describedor the processes herein referred to, the present invention is notconcerned with any particular process of production, but is for theproduct, however obtained.

Having thus described my invention, what I claim as new therein, anddesire to secure by Letters Patent, is---v 1. A substance possessing theherein-described physiological characteristics and reactions ofthesuprarenal glandsin a stable and concentrated form, and practically freefrom inert and associated gland-tissue.

2. A substance possessing the herein-described physiologicalcharacteristics and reactions of the suprarenal glands in a stable andconcentrated form, practically free from inert and associatedgland-tissue, and having a whitish color when in a dry orsolid'condition.

3. A crytalline substance possessingthe herein-described physiologicalcharacteristics and reactions of the suprarenal glands in a stable andconcentrated form, and practically free from inert constituents.

l. A substance possessing the herein-described physiologicalcharacteristics and reactions of the suprarenal glands in a stable andconcentrated form, having a whitish color and a crystalline form when ina dry or solid condition, and melting at about 207 centigrade.

having an alkaline reaction,

5. A substance in' theform of powder possessing the herein describedphysiological characteristics and reactions of the suprarenal-glands, instable and concentrated form, diflicultly soluble in water at ordinarytemperature, and readily soluble in acids or alkalies. 1

6. A crystalline substance possessing the herein-described physiologicalcharacteristics and reactions of the suprarenal glands,.said substancehaving the property of crystalli zing in a variety of forms.

7. A substance possessing the herein-described properties of thesuprarenal glands, having awhitish color, difficultly soluble in waterat ordinary temperature, soluble in acids and forming salts therewith,soluble in alkalies, and'melting at about 207 centigrade. 7

8-. A substance possessing the herein-described physiologicalcharacteristics and reactions of the suprarenal glands, havingapproximately the formula O H NO and having an alkaline reaction. g

9. A substance possessing the herein-described physiological-.characteristics and reactions of the suprarenal glands, practicallyfree from inert and associated gland-tissue,

and having an alkaline reaction. w

'10. A substance possessing the herein-described p'hysiologicalcharacteristics and reactions of the suprarenal glands, practically freefrom inert and associated gland-tissue, difficultly soluble in water,and giving a green coloration with an aqueous solution of a ferric salt.v

11. A substance possessing the herein-described physiologicalcharacteristics and reactions of the suprarenal glands, practically freefrom inert and associated gland-tissue, having an alkaline reaction andreducing properties.

12. A substance possessing the herein-described physiologicalcharacteristics and reactions of the suprarenal glands, practically freefrom inert and associated gland-tissue,

giving a green coloration in reaction with ferric salts,-anda redcoloration with iodin.

13.. A substance possessing the herein-described physiologicalcharacteristics and reactions of the suprarenal glands and which is notprecipitated by the usual alkaloid test reagents. V e

14. A substance possessing the herein-described properties of thesuprarenal glands, practically free from inert and associatedgland-tissue, having an alkaline reaction,

sure-raising properties having a Whitishcolor and a crystalline form,difiicultly soluble in water at ordinary temperature, soluble in acidsoralkalies, possessing reducing-properties, giving a green coloration inreaction with ferric salts and a red coloration in reaction with iodin.

16. A solution possessing the herein-described physiologicalcharacteristics and reactions of the suprarenal glands in concentratedand stable condition, and from which solution is obtained theherein-described substance free from inert and deteriorating matter bysimply neutralizing or removing the 'o solvent.

JOKICHI TAKAMINE.

Witnesses:

J. GREEN, 0. VON GRUEBER.

